2 lower alkyl-3-(4-phenyl-4-carboalkoxy piperidine) lower alkyl-5, 6 substituted indoles



United States Patent This invention relates to new indole compounds.More particularly this invention relates to new alkyl indoles and to themethod by which they are prepared.

The new compounds of the present invention are repre sented in theirbroadest aspect by the structural formula which follows:

C 6 (0 Hi) n-N I CO2R wherein R and R are selected from the groupconsisting of H and OCHg and R and R taken together are OCH O-; R isselected from the group consisting of H and CH R is lower valkyl havingnot more than 3 carbon atoms; n has a value of from 2 to 3 inclusive andthe pharmaceutically acceptable acid salts thereof. In the foregoingdescription, it is understood that R and R may be like or unlike,depending on the structure of the compound used in the preparation ofthe final prodnot.

The reaction sequence which follows, based on Example I, portrays apreferred method of making the compounds of the present invention. It isto :be understood that the specific reactants utilized are forillustrative purposes only and are not to be construed as limiting thescope of the invention either with respect to the new compounds or themethod by which they are prepared.

(1) MeSOzCl/pyr. (2) Norpethidine H IV According to the foregoingreaction sequence, it will be noted that aniline, or a substitutedaniline compound, as is shown, is first reacted with a halogenatedketoacid alkyl ester, such as for example 3-bromo-4 ketovaleric acidethyl ester, by heating the same together at a temperature of from about170 to about 190 C. for a period of from about 5 to about 20 minutes.The reaction mixture is then cooled and poured onto icy hydrochloricacid. The resulting indole ester 11 precipitated after purification isthen dissolved in an inert solvent such as tetrahydrofuran or dioxan anddropped into a slurry of LiAlH, in tetrahydrofuran. An exothermicreaction occurs after which the reaction mixture is diluted with etherand decomposed with water. The ether-tetra hydrofuran phase furnishes anoil, the hydroxyalkylindole III, which is then dissolved in a solventsuch as pyridine, and to which is added methanes-ulfonyl chloride. Thismixture on standing results in a chloroalkyl indole which is treated4-phenyl-4-carbalkoxypiperidine at a temperature of about 30 C. andpermitted to stand for 5-15 hours. The product, in the form of the freebase, is then taken up in an ether solvent. The desired final product IVis recovered on treating with dilute mineral acid in the conventionalmanner.

As has been suggested, the new compounds of the present invention arevaluable for their pharmaceutical properties. More specifically, the newcompounds of the present invention are useful as analgesics. When usedfor this purpose, the compounds of the present invention are preferablyformed into .a pharmaceutical preparation.

The lattercontains the specified. compound in admixture with apharmaceutically administrable organic or inorganic carrier, such thatthe composition is suitable for internal or parenteral administration.The composition may be prepared in solid form, such as in tablets, or inliquid form such as a solution, suspension or emulsion. Suitable liquidcarriers include water, gelatin, lactose, starch, talc, vegetable oils,alcohols, polyalcohols, gums, U.S.-P. syrups and the like. Thepharmaceutical composition in addition to the active principle and thecarrier may include auxiliary materials such as coloring, stabilizing,wetting or emulsifying agents. It is of course recognized as essentialthat the carrier as well as any other materials present with the activeprinciple be inert with respect thereto.

When the pharmaceutical preparation is compounded in the mannersuggested above, the active compound will be present in an amount offrom about 1 to about 500 mg/c. of the vehicle. Preferably the activecompound will be present in an amount of from 1 to about mg./cc. of thecarrier. When so prepared, the new compounds may be administered intherapeutic dosages of from about 16 to about 100 mg.

Reference to the specific examples which follow will provide a betterunderstanding of the new compounds of the present invention and themethod by which they are prepared.

. Example I 3,4-Dimethoxyaniline (13.2 g.=0.086 mole) is com 'bined with3-bromo-4-ketovaleric acid ethyl ester (9.6 g.=0.043 mole) and heated inan oil bath at 180 C. for 7 minutes. The reaction mixture is cooled andpoured onto icy hydrochloric acid. The gummy precipitate isether-extracted which results in an oil (7.2 g.; 60.5% yield) afterevaporation of the ether. The gummy residue is t-riturated with coolethanol to furnish the indole ester,2-methy1-5;6-dimethoxy-3-indolylacetic acid ethyl ester, (II) (2.66 g.)M.P. 81.5 8? C. UV spectrum possessed maxima at 224, 280, 298, 304 and308 m. IR spectrum showed the expected bands at 3.03 (NH), 5.87,u(ester).

The indole-ester (II) (12 g.) is then dissolved in tetrahydrofuran ml.)and dropped into a slurry of LlAlH4 (1.60 g.) in tetrahydrofuran (300ml.). After the slightly exothermic reaction subsides it is stirred foranother hour at room temperature. The reaction mixture is then dilutedwith ether (750 ml.) and decomposed with water. Theether-tetrahydrofuran phase furnishes an oil, 9.7 g. (95%), which isrecrystallized from benzene-petroleum ether; M.P. 126-128" C. UVspectrum had maxima at 228 and 305 mu. IR spectrum possessed theexpected bands at 2.93a (NH), 3.07 1. (OH) and had no absorption in theoxo-region. This product, Z-methyl- 5,6-dimethoxy-tryptophol (III) (3.5g.=0.0l41) is dissolved in pyridine (10 ml.) and methanesulfonylchloride (1.78 g.=1.2 ml. 0.0155 mole) is added at once. The reactionmixture is permitted to stand for hours, forming correspondingchloroethyl compound 2-methyl-3-fichloroethyl-5,6-dimethoxy-indole whichis thereupon treated with 4-phenyl-4-carbethoxypiperidine(Norpethidine). (It is liberated from 12.5 g. (=0.0456 mole) ofnorpethidine hydrochloride). The reaction mixture is heated to 32 C. andallowed to stand overnight at room temperature. It is taken up in etherand washed with water. The ether layer, containing the free base, istreated with diluted hydrochloric acid and crystalsof 2- methyl3-l3-(4-phenyl-4-carbethoxypiperidiuo)ethyl-5,6- dimethoxyindolehydrochloride (IV) separates out. M.P. is 191.5-92.5 C. UV spectrumpossessed maxima at 227, 305, and 311 mu. IR spectrum had the expectedbands at 3.10a (NH), 3.604.25/.L (salt band) and 5.78a (ester). Found:C, 66.87; H, 7.16; -N, 5.68%. C H N O Cl requires: C, 66.60; H, 7.24; N,5.75%.

Example II Following the procedure of Example I, using indole-3- ethanolin place of 2-methyl-5,G-dimethoxy-tryptophol, results in3-[3-(4-phenyl-4-carbethoxypiperidino)ethylindole.

Example III Following the procedure of Example I, but using 2-methy1-3-fi-hydroxyethyl-5,6-methylenedioxyindole, which is preparedfrom ,3,4-methylenedioxyaniline, 2-methyl-3- B(4-phenyl-4-carbethoxypiperidino)ethyl-5,6-methylenedioxyindole isprepared.

Example IV By using 5-methoxy-2-methyltryptophol in the method ofExample I,2-rnethyl-3-B-(4-phenyl-4-carbethoxypiperidino)ethyl-S-methoxyindole isproduced.

Example V 4 benzoic, methyl sulfonic, p-tolyl sulfonic, benzenesulfonic, naphthalene sulfonic, salicylic, glycolic, acetic, maleic,succinic, tartaric, stearic, palmitic, citric, glutaric, lactic and likeacids.

While the foregoing invention has been described with some degree ofparticularity in the specific example and the results set forth in thetable, it is to be understood that the invention is not to be limitedhereby but is only to be limited by the claims appended hereto.

The invention claimed is:

1. A member of the group consisting of a compound of the formula:

wherein R and R are selected from the group consisting of H and OCH andR and R taken together are OCH O; R is selected from the groupconsisting of H and CH R is lower alkyl having not more than 3 carbonatoms; n has a value of from 2 to 3 inclusive and the pharmaceuticallyacceptable acid addition salts thereof.

2. A compound of the formula:

wherein R and R are selected from the group consisting of H and OCH andR and R taken together are OCH O-; R i selected from the groupconsisting of H and CH R is lower alkyl having not more than 3 carbonatoms; and n has a value of from 2 to 3 inclusive.

3. 2 methyl 3 fi-(4-phenyl-4-carbethoxypiperidino)ethyl-5,6-dimethoxyindole.

4. 3 B-(4-phenyl-4-carbethoxypipeirdino)ethylindole.

5. 2 methyl I l-,6-(4-phenyl-4-carbethoxypiperidino)ethyl-5,6-methylenedioxyindole.

6. 2 methyl 3-,B(4-phenyl-4-carbethoxypiperidino) ethyl-S-methoxyindole.

7. 2 methyl 3[3-(4-phenyl-4-carbomethoxypiperidino)propyl-S,6-dimethoxyindole.

References Cited by the Examiner UNITED STATES PATENTS 3,097,208 7/1963Elpern 260--294.3 X 3,112,308 11/1963 Lowrie 260243 3,183,235 5/1965Zenitz 260-294 OTHER REFERENCES Hardy et al.: chapter V, Analgetics,Medicinal chemistry, vol. 5, of a series of monographs, 187 and 191;edited by De Stevens, Academic Press, 1965, New York.

WALTER A. MODANCE, Primary Examiner.

AVROM D. SPEVACK, Assistant Examiner,

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: